Amiloride

Amiloride is a medication primarily known as an anti-kaliuretic and epithelial sodium channel blocker, but it also has various other applications in treating different conditions. It has been used clinically for decades in the management of hypertension and as a pharmacological tool for examining sodium transport .

Scientific Research Applications

Hypertension and Edema
this compound is used to treat hypertension and edema . A study showed that a daily 10 mg dose of this compound taken in the morning with breakfast for four weeks significantly reduced peripheral systolic blood pressure (SBP) by 7.06 ± 2.25 mmHg and diastolic blood pressure (DBP) by 4.35 ± 1.67 mmHg . Central SBP was reduced by 7.68 ± 2.56 mmHg, and central DBP by 4.49 ± 1.78 mmHg . There were also significant increases in flow-mediated dilation (FMD) and a reduction in carotid radial pulse wave velocity (CR-PWV), indicating improved endothelial function and lowered peripheral arterial stiffness .

In a case study, a patient with type 1 diabetes, severe hypertension (200/140 mmHg), progressive edema (of at least 10 L), and overt proteinuria (18.5 g/24 h) was treated with this compound (5 mg/day) in addition to other antihypertensive drugs . This resulted in the resolution of edema, a weight loss of 7 kg, and a reduction in blood pressure (150/100-125/81 mmHg) .

The AMILOR study, a monocentric randomized controlled pilot study, found that this compound had a similar antiedematous effect as furosemide in patients with edema .

Proteinuria
this compound can reduce proteinuria in patients with proteinuric kidney disease . A study involving 12 patients showed that this compound reduced 24-hour urine protein by 38.7% and decreased systolic blood pressure by 12.3 mm Hg .

Cystic Fibrosis
this compound has been researched in the context of cystic fibrosis because of its ability to inhibit epithelial sodium channels (ENaC) .

Pain Reduction

This compound can block proton-induced pain in humans . Simultaneous application of 200 μM this compound reduced acid-evoked pain almost to the pH 7.4 control level . Pretreatment with this compound significantly reduced irritant sensations elicited by citric acid on the dorsal surface of the tongue, but did not reduce capsaicin-evoked oral irritation, suggesting an this compound-sensitive mechanism in acid-induced irritation .

Cancer Treatment

This compound has demonstrated anti-cancer and anti-metastatic potential in vitro and in vivo . It has been shown to inhibit mutagen-induced carcinogenesis, tumor formation, and metastatic progression in rats and mice . These effects are generally attributed to the cytostatic effects of this compound inhibiting sodium hydrogen exchanger-1 (NHE1) and the motility-suppressing effects of urokinase plasminogen activator (uPA) inhibition .

A novel lipophilic C(5) this compound derivative, LLC1, can induce cell death in the single-digit micromolar range, selectively eradicating chemoresistant breast tumor cells .

Other Applications

This compound-based ligands have been identified as small molecules . this compound has been found to be ineffective at all doses tested, implicating opioid receptors, GC-C, and sodium and TRP channel activation as possible pharmacological reference compounds .

Data Table

Case Studies

Case Study 1: Hypertension and Edema
A 38-year-old male with type 1 diabetes developed severe hypertension (200/140 mmHg), progressive edema (at least 10 L), and overt proteinuria (18.5 g/24 h) despite being treated with five antihypertensive drugs . The addition of this compound at 5 mg/day to his treatment regimen resulted in the resolution of edema, a weight loss of 7 kg, and a reduction in blood pressure to 125/81 mmHg . The patient's 24-hour urinary sodium excretion increased (127-165 mmol/day), his eGFR decreased (41-29 mL/min), and his plasma potassium concentration increased (4.6-7.8 mmol/L) .

Case Study 2: Proteinuria
In a study of 12 patients with proteinuric kidney disease, this compound was administered at 5 mg twice daily . The results showed a 38.7% reduction in 24-hour urine protein and a 12.3 mm Hg decrease in systolic blood pressure . These findings suggest that this compound can be effective in reducing proteinuria and improving blood pressure control in patients with kidney disease .

Target of Action

Amiloride primarily targets the This compound-sensitive sodium channels located in the distal convoluted tubules and collecting ducts in the kidneys . These channels play a crucial role in sodium reabsorption, which is essential for maintaining electrolyte balance and blood pressure .

Mode of Action

This compound interacts with its targets by binding to the this compound-sensitive sodium channels, thereby inhibiting sodium reabsorption . This inhibition creates a negative potential in the luminal membranes of principal cells, reducing the secretion of potassium and hydrogen ions . The overall effect is a promotion of the loss of sodium and water from the body, without depleting potassium .

Biochemical Pathways

The inhibition of sodium reabsorption by this compound affects the sodium-potassium balance in the body. It disrupts the normal function of the sodium/potassium ATPase pump, which maintains the necessary electrochemical gradients . This disruption leads to an increase in sodium and water excretion while reducing potassium excretion .

Pharmacokinetics

This compound is readily absorbed and begins to act within 2 hours after an oral dose . Its effect on electrolyte excretion reaches a peak between 6 and 10 hours and lasts about 24 hours . Peak plasma levels are obtained in 3 to 4 hours, and the plasma half-life varies from 6 to 9 hours .

Result of Action

The molecular and cellular effects of this compound’s action include a decrease in sodium reabsorption and an increase in sodium and water excretion . This results in a reduction in potassium and hydrogen ion secretion . At the cellular level, this compound can cause changes in cell volume and electrolyte concentrations .

Action Environment

Environmental factors can influence the action, efficacy, and stability of this compound. For instance, the presence of other medications, the patient’s diet, and the patient’s health status (such as kidney function) can all impact how this compound works in the body . .

Biochemical Properties

Amiloride works by inhibiting sodium reabsorption in the distal convoluted tubules and collecting ducts in the kidneys by binding to the this compound-sensitive sodium channels . This promotes the loss of sodium and water from the body, but without depleting potassium .

Cellular Effects

This compound has been shown to have significant effects on various types of cells. It can cause changes to the levels of certain minerals in your body, called electrolytes. For example, it may cause high potassium levels (hyperkalemia), low sodium levels (hyponatremia), or low chloride levels (hypochloremia) .

Molecular Mechanism

This compound exerts its effects at the molecular level by binding to the this compound-sensitive sodium channels in the distal convoluted tubules and collecting ducts of the nephron . This binding inhibits sodium reabsorption, which in turn reduces the secretion of potassium and hydrogen ions .

Temporal Effects in Laboratory Settings

This compound is administered orally and reaches its peak diuretic effect at 6–10 hours . It does not undergo metabolism by the liver and is predominantly excreted unchanged in urine and faeces .

Dosage Effects in Animal Models

In animal models, such as dogs and cats, the dosage of this compound is typically around 0.1 mg/kg p.o. q12h . The effects of this compound can vary with different dosages, and high doses may lead to adverse effects such as hyperkalemia .

Metabolic Pathways

This compound does not undergo metabolism by the liver and is predominantly excreted unchanged in urine and faeces . It acts independently of aldosterone, inhibiting sodium reabsorption through epithelial sodium channels (ENaC) and preventing potassium excretion in the distal convoluted tubule and collecting ducts .

Transport and Distribution

This compound is transported and distributed within cells and tissues via the bloodstream. It acts at the distal convoluted tubule and collecting duct of the nephron to produce its diuretic effect .

Subcellular Localization

The subcellular localization of this compound is primarily at the distal convoluted tubules and collecting ducts of the nephron . It binds to the this compound-sensitive sodium channels in these areas, inhibiting sodium reabsorption and reducing the secretion of potassium and hydrogen ions .

Synthetic Routes and Reaction Conditions: Amiloride can be synthesized through a multi-step process involving the reaction of 3,5-diamino-6-chloropyrazine-2-carboxamide with various reagents. One common method involves the reaction of 3,5-diamino-6-chloropyrazine-2-carboxamide with cyanamide under acidic conditions to form this compound .

Industrial Production Methods: Industrial production of this compound typically involves large-scale synthesis using similar reaction conditions as in laboratory synthesis. The process is optimized for yield and purity, often involving purification steps such as recrystallization and chromatography to ensure the final product meets pharmaceutical standards .

Types of Reactions: Amiloride undergoes several types of chemical reactions, including:

Oxidation: this compound can be oxidized under specific conditions, although this is not a common reaction in its typical use.

Reduction: Reduction reactions are less common for this compound due to its stable structure.

Substitution: this compound can undergo substitution reactions, particularly at the amino groups.

Common Reagents and Conditions:

Oxidation: Strong oxidizing agents can be used, but these reactions are not typically relevant to its pharmacological use.

Substitution: Reagents such as alkyl halides can be used for substitution reactions at the amino groups under basic conditions.

Major Products Formed: The major products formed from these reactions depend on the specific reagents and conditions used. For example, substitution reactions can yield various alkylated derivatives of this compound .

Triamterene: Another potassium-sparing diuretic with a similar mechanism of action.

Spironolactone: A potassium-sparing diuretic that works by antagonizing aldosterone receptors.

Eplerenone: Similar to spironolactone but with fewer side effects.

Uniqueness of Amiloride: this compound is unique in its specific inhibition of the ENaC, which makes it particularly effective in conditions where sodium retention is a problem. Unlike spironolactone and eplerenone, this compound does not affect aldosterone receptors, which reduces the risk of hormonal side effects .

Amiloride is a potassium-sparing diuretic primarily used in the treatment of hypertension and heart failure. It selectively inhibits epithelial sodium channels (ENaC), leading to various biological effects beyond its diuretic action. This article explores the biological activity of this compound, focusing on its mechanisms of action, therapeutic applications, and recent research findings.

This compound's primary mechanism involves the inhibition of ENaC located in the distal nephron, lung, and colon. By blocking these channels, this compound reduces sodium reabsorption and promotes potassium retention, which is crucial in managing conditions like hypertension and edema. The molecular structure of ENaC consists of three subunits (α, β, and γ), and mutations in these subunits can lead to disorders such as Liddle syndrome, where ENaC activity is abnormally high .

Key Mechanisms:

• Inhibition of ENaC: Reduces sodium reabsorption.
• Impact on Acid-Sensing Ion Channels (ASICs): Involved in various physiological processes.
• Interaction with Na+/H+ Antiporters and Na+/Ca2+ Exchangers: Affects intracellular pH and calcium transport during cellular activation .

Therapeutic Applications

This compound has been investigated for several therapeutic uses beyond its traditional role as a diuretic:

• Hypertension Management: It is often combined with other diuretics to enhance blood pressure control.
• Edema Treatment: this compound has shown effectiveness in treating resistant edema in patients with conditions like nephrotic syndrome .
• Bone Health: Recent studies indicate that this compound inhibits osteoclastogenesis, suggesting potential applications in treating bone loss-related diseases .
• Cancer Research: this compound and its derivatives are being explored for their cytotoxic properties against various cancer cell lines, showing promise in targeting chemoresistant tumors .

Case Study 1: Resistant Edema

A study involving a 38-year-old male patient with type 1 diabetes revealed that the addition of this compound (5 mg/day) to his treatment regimen resolved severe edema and significantly reduced blood pressure from 200/140 mmHg to 150/100 mmHg after several days. The patient's urinary sodium excretion increased, indicating effective diuretic action .

Case Study 2: Osteoclastogenesis Inhibition

Research demonstrated that this compound effectively inhibited RANKL-induced osteoclast differentiation in vitro. The study showed a concentration-dependent decrease in TRAP-positive multinucleated cells, highlighting its potential as a therapeutic agent for diseases like osteoporosis .

Recent Research Findings

Recent studies have expanded the understanding of this compound's biological activity:

• Antiedematous Effects: The AMILOR study compared this compound with furosemide for treating edema. While both showed similar effects in reducing extracellular water over time, further research is needed to establish this compound's definitive role .
• Cancer Therapeutics: Investigations into this compound derivatives have revealed enhanced cytotoxicity against breast cancer cells while sparing normal cells. This specificity may be due to the modulation of lysosomal function and sodium-hydrogen exchanger inhibition .

Comparative Data Table